YTHDF2 inhibition potentiates radiotherapy antitumor efficacy

文献类型： 外文期刊

第一作者： Wang, Liangliang

作者： Wang, Liangliang;Huang, Xiaona;Wang, Jiaai;Yang, Kaiting;Bugno, Jason;Pitroda, Sean;Piffko, Andras;Chmura, Steven J.;Liang, Hua Laura;Weichselbaum, Ralph R.;Wang, Liangliang;Huang, Xiaona;Wang, Jiaai;Yang, Kaiting;Bugno, Jason;Pitroda, Sean;Piffko, Andras;Liang, Hua Laura;Weichselbaum, Ralph R.;Dou, Xiaoyang;Yu, Xianbin;Zhang, Linda;He, Chuan;Dou, Xiaoyang;Yu, Xianbin;Zhang, Linda;He, Chuan;Dou, Xiaoyang;Yu, Xianbin;Zhang, Linda;He, Chuan;Chen, Shijie;Chen, Yantao;Chen, Chao;Jiang, Hualiang;Zhou, Bing;Luo, Cheng;Bugno, Jason;Ding, Xingchen;Piffko, Andras;Si, Wei;Luo, Cheng;He, Chuan

作者机构：

期刊名称：CANCER CELL （ 影响因子：50.3； 五年影响因子：43.9 ）

ISSN： 1535-6108

年卷期： 2023 年 41 卷 7 期

页码：

收录情况： SCI

摘要： RNA N6-methyladenosine (m6A) modification is implicated in cancer progression. However, the impact of m6A on the antitumor effects of radiotherapy and the related mechanisms are unknown. Here we show that ionizing radiation (IR) induces immunosuppressive myeloid-derived suppressor cell (MDSC) expansion and YTHDF2 expression in both murine models and humans. Following IR, loss of Ythdf2 in myeloid cells aug-ments antitumor immunity and overcomes tumor radioresistance by altering MDSC differentiation and inhib-iting MDSC infiltration and suppressive function. The remodeling of the landscape of MDSC populations by local IR is reversed by Ythdf2 deficiency. IR-induced YTHDF2 expression relies on NF-KB signaling; YTHDF2 in turn leads to NF-KB activation by directly binding and degrading transcripts encoding negative regulators of NF-KB signaling, resulting in an IR-YTHDF2-NF-KB circuit. Pharmacological inhibition of YTHDF2 over-comes MDSC-induced immunosuppression and improves combined IR and/or anti-PD-L1 treatment. Thus, YTHDF2 is a promising target to improve radiotherapy (RT) and RT/immunotherapy combinations.

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